TOUCH MEDICAL MEDIA30

Review Colorectal Cancer

Primary Tumor Location Implications on Biological Therapy in Metastatic Colorectal CancerMarwan Fakih

Medical Oncology, Gastrointestinal Oncology, City of Hope Comprehensive Cancer Center, California, US

A nti-epidermal growth factor receptors (anti-EGFRs) have been clinically proven to improve overall survival (OS) when combined with chemotherapy in the settings of extended RAS wild-type metastatic colorectal cancers. In addition, randomized phase III studies have confirmed the superiority of anti-EGFR therapy over bevacizumab in the front-line treatment of extended RAS wild-type metastatic

colorectal cancer when it comes to response rate, and in select studies, OS. Recent updates from these clinical trials project convincing evidence that tumor sidedness is yet another predictive marker for response to anti-EGFR therapy. While left colonic RAS wild-type metastatic colorectal cancers derive major clinical benefit from anti-EGFR versus bevacizumab therapy, bevacizumab appears to have clear advantage in RAS wild-type metastatic right-sided tumors. In this review, we summarize recent reports from key clinical trials and their impact on day-to-day clinical practice.

Keywords

Sidedness, colorectal cancer, epidermal growth factor, metastatic disease, cetuximab, panitumumab, bevacizumab, chemotherapy

Disclosure: Marwan Fakih has nothing to declare in relation to this article. This study involves a review of the literature and did not involve any studies with human or animal subjects performed by any of the authors. No funding was received for the publication of this article.

Authorship: All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole and have given final approval for the version to be published.

Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit.

Received: February 20, 2017

Accepted: April 7, 2017

Citation: Oncology & Hematology Review, 2017;13(1):30–3

Corresponding Author: Marwan Fakih, City of Hope Comprehensive Cancer Center, 1500 E Duarte Rd, Duarte, CA 91010, US. E: mfakih@coh.org

Several studies have shown a survival advantage with the addition of anti-epidermal growth factor

receptor (anti-EGFR) therapy to chemotherapy in molecularly selected patients with advanced

colorectal cancer. The Panitumumab Randomized trial in combination with chemotherapy for Metastatic

colorectal cancer to determine Efficacy (PRIME) clinical trial investigated the addition of panitumumab

to folinic acid, fluorouracil, and oxaliplatin (FOLFOX) in patients with KRAS exon-2 wild-type metastatic

colorectal cancer.1 The addition of panitumumab to chemotherapy improved overall survival (OS) by

17% and translated in a statistically significant increase in median OS from 19.7 to 23.9 months.1

Further analysis confirmed a lack of benefit from panitumumab in exon-3 and exon-4 KRAS mutations

and exon 2, 3, and 4 NRAS mutations, therefore limiting panitumumab recommendations to extended

RAS wild-type metastatic colorectal cancer. In this subgroup of patients, panitumumab improved

the OS by 22%, extending the median OS from 20.2 to 26.0 months.2 Similar findings have been

reported in the Cetuximab combined with iRinotecan in first-line therapY for metastatic colorectal

cancer (CRYSTAL) trial, a randomized phase III clinical trial comparing folinic acid, fluorouracil, and

irinotecan (FOLFIRI) to FOLFIRI plus cetuximab in the first-line treatment of KRAS wild-type metastatic

colorectal cancer. The addition of cetuximab to FOLFIRI improved OS by 20% and was associated with

a significant improvement in median survival from 20.0 to 23.5 months.3 Further analysis confirmed a

lack of benefit from non-exon 2 KRAS and exons 2, 3, and 4 NRAS mutations. The addition of cetuximab

to FOLFIRI in RAS wild-type metastatic colorectal cancer improved OS by 31%.4 These studies, and

other supporting evidence from second-line (and beyond) clinical trials support the benefit from anti-

EGFR therapy in extended RAS wild-type colorectal cancer.5 Additional evidence suggests that BRAF

mutations, in addition to their poor prognostication, are also associated with lack of clinical benefit

from anti-EGFR therapy.6 Recent studies, however, suggest that in addition to RAS and BRAF status,

tumor sidedness has a considerable impact on metastatic colorectal cancer outcome, specifically

with anti-EGFR therapy. In this review, we review pertinent literature on right and left colon cancer

and its impact on anti-EGFR therapy recommendations in patients with advanced colorectal cancer.

Biological differences between right and left colonThe right and left colons are embryologically distinct. The right colon is derived from the midgut and

consists of the cecum, ascending colon, and the proximal two-thirds of the transverse colon. The left

colon is derived from the hindgut and extends from the end of the transverse colon cancer to the

rectum.7 Indeed, the biological differences between the right and the left colon have been shown to

exist at the molecular level—as confirmed by extensive gene expression studies on colonic tissue

from human embryos and adults.8 Therefore, it is not surprising that distinct molecular differences have

been seen between right and left colorectal cancers across different genomic data sets. Missaglia et

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DOI: https://doi.org/10.17925/OHR.2017.13.01.30

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Primary Tumor Location Implications on Biological Therapy in Metastatic Colorectal Cancer

al. reported on the biology of colorectal cancers from the PETACC-3 and the

TCGA data sets.9 Right colonic tumors were more likely to be microsatellite

instable (MSI) or MSI-like, associated with a RAS or a BRAF signature, have

a serrated pathway, and to have a JAK-STAT gene signature. Left colonic

tumors were more likely to be associated with WNT and MYC pathways

activation, to have beta catenin activation, and to be associated with EGFR

and HER2 upregulation. Even upon limiting the analysis to patients with

microsatellite stability (MSS), KRAS wild-type, and BRAF wild-type tumors,

left colonic tumors were associated with EGFR upregulation, which was

lacking in right colonic tumors. These major variations between left and

right colonic cancers, particularly at the EGFR expression and activation

level, provide support to the subsequent clinical data that suggest a lack

of anti-EGFR activity in right colonic tumors, irrespective of RAS status. It

is likely that left colonic tumors, in contrast to right colonic tumors, are

dependent on an overactive EGFR-pathway, making them more susceptible

to EGFR blockade as a therapeutic strategy.

Prognostic implications of right and left colon cancersSeveral studies have shown that the OS of colorectal cancer patients is

negatively impacted by right sidedness. However, considerable debate

remains around the interaction between tumor location and stage vis-à-vis

OS. Both Weiss et al., and Meguid et al. reported on sidedness and outcome

based on analyses of the Surveillance, Epidemiology, and End Results (SEER)

data base.10,11 Both studies showed a worse outcome in patients with right

colonic tumors, particularly those with stage III disease. Other population-

based studies reported on the OS of stage I–III colon cancers and generated

conflicting results as to the impact of sidedness on outcome.12–14 Recent

analysis of prospective clinical trials sheds additional light on the impact of

sidedness in earlier stage disease, specifically in stage III colon cancer. The

PETACC-3 clinical trial randomized 3,045 patients with stage III disease to

receive fluorouracil (5-FU) and leucovorin (LV) versus FOLFIRI in the adjuvant

setting. No difference in OS was noted between the two treatment arms.

Patients with right colon tumors had similar rates of relapse as patients

with left colon. However, once a patient relapsed, the OS was clearly

impacted by sidedness, with an inferior outcome being noted in right-

sided cancers.9 Similarly, a combined analysis of two randomized phase

III clinical trials (Vioxx in Colorectal Cancer Therapy [VICTOR] and Adjuvant

capecitabine plus bevacizumab versus capecitabine alone in patients with

colorectal cancer [QUASAR-2]) failed to show a difference in relapse free

survival (RFS) between right and left colons while confirming a significantly

worse outcome in survival postrelapse in right versus left colon cancers.15

The above studies suggest that the impact of sidedness on outcome is

more relevant following the development of metastatic disease, reflecting

a possible difference in biology and response to therapy following the

development of distant metastases. Such hypothesis is clearly supported

by a recent meta-analysis of first-line metastatic disease clinical trials

which showed a consistent and significant worsening in OS in metastatic

colorectal cancer originating in the right colon.16 Since the poor OS in

metastatic right colon cancer has been reported in studies that precede the

use of anti-EGFR therapy, one cannot attribute the divergence in outcome

to a difference in anti-EGFR response alone.

Anti-epidermal growth factor recepter therapy and sidednessThere is mounting clinical evidence that anti-EGFR response can be

predicted by tumor sidedness in patients with RAS wild-type metastatic

colorectal cancer. In this section, we review supportive clinical evidence

originating from retrospective patient-series and from the retrospective

analysis of prospectively conducted clinical trials.

Chemotherapy-refractory colorectal cancerMoretto et al. recently reported on the outcome of 75 RAS wild-type patients

with irinotecan-resistant colorectal cancer.17 Only 14 out of 75 patients had

right colon cancer and were treated with anti-EGFR alone (10 patients) or

anti-EGFR + irinotecan (four patients). None of the right-sided colon cancer

patients experienced a response and only two had stable disease as best

response. Sixty-one patients with left colon cancer were treated with anti-

EGFR monotherapy (75%) or anti-EGFR plus irinotecan. Forty percent of

patients with left-sided tumors experienced an objective response and

an additional 39% had stable disease. Significant differences were noted

between the right and the left colon in terms of progression free survival

(PFS) (2.3 versus 6.6 months) and OS (6 versus 15.3 months). These data

suggest limited efficacy for anti-EGFR in the treatment of RAS wild-type

refractory right colorectal cancer. In an earlier study, de Roock reported on

203 patients with RAS and BRAF wild-type irinotecan-refractory metastatic

colorectal cancer who were treated with cetuximab plus irinotecan.18

Patients with right colon cancer (n=45) experienced a much shorter time

to progression (hazard ratio [HR]=1.48, p=0.02) than patients with left colon

cancer (n=158). Last, a retrospective analysis of the pivotal CO.17 clinical

trial randomizing patients with chemotherapy-resistant metastatic colon

cancer to cetuximab or best supportive care reported on the outcome of

KRAS wild-type right and left colon cancers (Table 1).19 Benefits in PFS and

OS were limited to patients with left-sided tumors. Only 56 patients with

right colon cancer were subject to analysis in this study, and despite a lack

of a survival advantage in right colon tumors, the median OS was 6.2 versus

3.5 months in favor of patients receiving cetuximab.19 Taken in total, the

above studies suggest minimal to no benefit with anti-EGFR therapy in

right colon cancer. It is important to note that the sample size limitations

do not allow for the exclusion of a possible small survival advantage from

anti-EGFR therapy or the possibility of substantial benefit from anti-EGFR

therapy in a select, but small, population with right colonic tumor and RAS

wild-type tumors. The benefits in left colonic RAS wild-type tumors on the

other hand are clear and the clinical benefits are substantial.

First- and second-line metastatic colorectal cancerIn a retrospective study, Wang et al. described the outcome of 416 patients

receiving chemotherapy plus cetuximab or chemotherapy alone in the

first-line and second-line treatment of metastatic colorectal cancer.20

Efficacy outcomes from response rate (RR) to OS were improved in

patients receiving chemotherapy and cetuximab over chemotherapy

in first- and second-line setting in left colon tumors. No benefits were seen

Table 1: Clinical outcome among KRAS wild-type metastatic colorectal cancers by tumor location on CO.17 clinical trial

Right Colon

KRAS Wild-Type

Left Colon

KRAS Wild-Type

Cmab BSC (n=27) Cmab (n=60) BSC (n=45)

PFS 1.9 m 1.9 m 5.4 m* 1.8 m

OS 6.2 m 3.5 m 10.1 m* 4.8 m

Cmab = cetuximab; BSC = best supportive care; PFS = progression free survival; OS = overall survival; m = months; * (denotes statistical significance; p<0.05).

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Review Colorectal Cancer

with cetuximab in right colonic tumors. More conclusive evidence comes

from retrospective analyses of first-line randomized clinical trials. Five

randomized first- and second-line phase III studies have now published

or presented on the outcome of patients with RAS wild-type metastatic

colon cancer in the setting of anti-EGFR therapy by primary tumor

location. The CRYSTAL and PRIME clinical trials reported on the outcome of

first-line chemotherapy with or without cetuximab and panitumumab,

respectively. On the CRYSTAL trial, adding cetuximab to chemotherapy

significantly improved RR (72.5% versus 40.6%), PFS (12 versus 8.9 months),

and OS (28.7 versus 21.7 months) over chemotherapy alone only in patients

with left colon tumor (Table 2).21 Similar superior results were noted in left

colonic tumors on the PRIME clinical trial, with RR (70.3% versus 54.8%), PFS

(12.9 versus 9.3 months), and OS (32.5 versus 23.6 months) (Table 2).22 No

benefit, but no detrimental impact, was noted when anti-EGFR therapy was

added to chemotherapy in right colonic tumors. These clinically relevant

improvements strongly support the incorporation of either cetuximab or

panitumumab in the front-line treatment of RAS wild-type left colon with

metastatic disease. Similar trends have been demonstrated in the 181

second-line study of FOLFIRI with our without panitumumab when limiting

the analysis to RAS wild-type colon cancer (Table 2).22 Patients with left

colon cancer experienced a significant improvement in RR (50.7% versus

13.5%), with a trend of improvement in PFS (8 versus 6.6 months) and OS

(20.1 versus 16.9 months). No benefits were noted in any efficacy measures

with panitumumab in right colonic tumors.

Given the prevalent use of anti-angiogenic therapy in the first- and

second-line treatment of metastatic colorectal cancer, a head-to-head

comparison of anti-EGFR therapy to anti-angiogenesis therapy is a more

relevant question in today’s day-to-day practice. The FIRE-3 clinical trial

randomized 592 patients with KRAS wild-type metastatic colorectal cancer

to FOLFIRI plus bevacizumab versus FOLFIRI plus cetuximab.23 While this

study failed its primary endpoint of RR, significant improvements in OS

were noted in favor of cetuximab that were accentuated further in the RAS

wild-type population. In a post hoc analysis of FIRE-3 outcome by colon

side, a significant improvement in OS was limited to the left colon tumor

patient population (38.3 versus 28 months; HR=0.63, p=0.02).21 Patients

with right colon cancer had a trend toward a worsened OS outcome

with cetuximab versus bevacizumab (18.3 versus 23 months; HR=1.44,

p=0.28).21 Similar trends were noted recently on Cancer and Leukemia

Group B (CALGB 80405), a randomized clinical trial of chemotherapy

(FOLFOX or FOLFIRI) with cetuximab versus bevacizumab in the first-line

treatment of KRAS wild-type metastatic colorectal cancer.24 No difference

in PFS or OS was noted between arms, although cetuximab was associated

with improved RR.24 However, a significant biologic interaction was noted

by sidedness for both PFS and OS.25 Significant improvements in OS were

noted in favor of cetuximab (39.3 versus 32.7 months; HR=0.77, p=0.04)

in the left colonic tumors while cetuximab was associated with a worse

outcome for both PFS (7.5 versus 10.2 months; HR=1.64, p=0.006) and

OS (13.7 versus 29.2 months; HR=1.36, p=0.10) in right colonic tumors.25

These data, in line with FIRE-3, suggest an advantage for incorporating

anti-EGFR therapy over bevacizumab in left colonic metastatic cancers

while significant concerns arise from a potential harm, or at least, lack of

benefit from anti-EGFR therapy in the first-line treatment of right colonic

metastatic cancer.

ConclusionsRetrospective analysis of multiple randomized phase III clinical trials point

to the effectiveness of anti-EGFR therapy across lines of treatment in RAS

wild-type metastatic colorectal cancer. The significant improvements in

OS across FIRE-3 and CALGB 80405 in the first-line setting in left colon

cancers suggest that this biologic class of agents should be the favorite

choice when considering targeted therapy in this left colon cancer patients

(Figure 1). BRAF-mutated colon cancers, while representing a very small

portion of left colon cancers, are not known to benefit from anti-EGFR

therapies and can be considered for alternative strategies, including folinic

acid, fluorouracil, oxaliplatin, irinotecan, plus bevacizumab (FOLFOXIRI-

BV).26 Of note, the current evidence-based data apply to doublet

combination chemotherapy backbones. While anti-EGFR therapies appear

to be superior to bevacizumab when combined with FOLFOX or FOLFIRI, we

have no comparative data for FOLFOX plus panitumumab or FOLFIRI

plus cetuximab to FOLFOXIRI-BV. Given the significant improvements

noted with FOLFOXIRI-BV over FOLFIRI-BV across different molecular

subgroups of metastatic colorectal cancer, FOLFOXIRI-BV remains an

appropriate choice for left (and right) colonic RAS wild-type metastatic

colorectal cancer.26 Finally, some left colon cancer patients may not find the

potential side effects of anti-EGFR therapy palatable in a first-line setting.

In those patients, a bevacizumab-based backbone therapy is appropriate,

irrespective of chemotherapy backbone.

The current evidence suggests that RAS wild-type right colonic tumors

should not receive anti-EGFR therapy in the first- and second-line settings

Table 2: Clinical outcome among RAS wild-type metastatic colorectal cancers by tumor location across select randomized first- and second-line phase III clinical trials

Study OS (Left Colon) OS (Right Colon)

EGFRi Control EGFRi Control

1st Line CRYSTAL 28.7 (HR=0.65)* 21.7 m 18.5 m (HR=1.08) 15 m

PRIME 32.5 (HR=0.67)* 23.6 m 22.5 m (HR=0.94) 21.5 m

EGFRi

versus BV { FIRE-3 38.3 (HR=0.63)* 28 m 18.3 m (HR=1.44) 23 m

80405 39.3 (HR=0.77)* 32.7 m 13.7 m (HR=1.36) 29.2 m

2nd Line 181 20.1 (HR=0.97) 16.9 m 11.9 m (HR=0.84) 10.9 m

OS = overall survival; EGFRi = epidermal growth factor inhibitor (cetuximab or panitumumab): BV = bevacizumab; HR = hazard ratio; m = months; * (denotes statistical significance: p<0.05).

MT = mutated; WT = wild-type; BV = bevacizumab; EGFRi = epidermal growth factor receptor inhibitor (cetuximab or panitumumab); FOLFOXIRI = folinic acid, fluorouracil, oxaliplatin, irinotecan.

Figure 1: First-line treatment algorithm in good performance patients with metastatic colorectal cancer

RAS MT

FOLFOXIRI + BV is a treatment option across all molecular subtypes

BRAF MTRAS WT/BRAF WT

MetastaticColorectal

Cancer

BV+Chemotherapy

BV+Chemotherapy

Right ColonBV+

Chemotherapy

Left ColonEGFRi

Chemotherapy

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Primary Tumor Location Implications on Biological Therapy in Metastatic Colorectal Cancer

(Figure 1). The exclusion of BRAF mutations from this subgroup does not

unearth a clinical benefit in the RAS/BRAF wild-type patients.21 While

a survival advantage is missing with anti-EGFR in front-line treatment

settings, one must acknowledge the limitations of this evidence given

the small right colonic data sets. The presence of a small trend toward

improvement in OS with cetuximab monotherapy in KRAS wild-type right

colonic tumors as well as the trends in improved RR on the CRYSTAL

and PRIME in right colonic tumors, suggest a potential benefit of anti-

EGFR in a small subgroup of right colonic tumors. Defining additional

biomarkers of response to anti-EGFR therapy in right colonic patients

will be important to optimize our personalized treatments with anti-

EGFR therapy. Until then, anti-EGFR therapies should be avoided in first-

and second-line therapies. However, until we have further conclusive

evidence in chemorefractory settings, I am not ready to completely

exclude this therapeutic option in our chemorefractory RAS/BRAF wild-

type colonic patients.

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